Molecular Genetics of Cardiac Myxomas (Carney Complex)

描述（由申请人提供）：心脏粘液瘤是最常见的原发性心脏肿瘤。它们是良性肿瘤，通过栓塞、心力衰竭和全身症状引起发病和死亡。大约7%的心脏粘液瘤患者有家族性综合征，Carney综合征，一种常染色体显性遗传疾病，其中心脏粘液瘤发生在皮肤色素沉着和内分泌病的背景下。这种心脏粘液瘤可以发生在所有的心腔，可能是多中心的，并且经常复发。我们在人类染色体17 q24上发现了一个主要的疾病位点，并表明PRKAR 1 a（蛋白激酶A的R1亚基）基因突变在近2/3的患者中引起Carney综合征。大多数PRKARla突变导致单倍不足。Carney复合体中的PRKARla依赖性肿瘤发生似乎需要额外的体细胞突变。虽然PRKARla杂合性丢失偶尔发生，但其他尚未鉴定的基因必须在Carney复合体和心脏粘液瘤的发病机制中发挥作用。在卡尼复杂的心脏肿瘤发生的机制的描绘需要识别这些基因和表征的实验模型，在其中研究它们。我们现在已经确定了一个新的基因座（“CAR 2”），其几率为24，500：1，包含第二个Carney复合体疾病基因。此外，我们发现prkarla单倍不足小鼠表现出心房肌细胞核肥大和内脏间质肿瘤。因此，我们提出[1]鉴定引起Carney复合体和心脏粘液瘤的CAR 2基因，[2]表征与鼠prkarla相互作用引起肿瘤发生的基因，和[3]评估Carney复合体基因的体细胞突变对非家族性、孤立的人类心脏粘液瘤的贡献。我们将使用位置克隆候选策略来鉴定CAR 2 Carney复合体疾病基因中的突变。我们将研究不同遗传背景和其他肿瘤抑制基因的基因剂量改变对小鼠prkarla依赖性肿瘤发生的影响。这些研究将建立导致Carney复合体中心脏和其他器官肿瘤发生的分子遗传途径，并将为常见的非家族性心脏粘液瘤的发病机制提供候选基因。研究结果将突出心脏粘液瘤治疗的潜在靶点，以改变常见心血管疾病（如心力衰竭和缺血性心脏病）的心脏重塑。

DESCRIPTION (provided by applicant): Cardiac myxomas are the most common form of primary cardiac tumor. They are benign neoplasms that cause morbidity and mortality through embolism, heart failure, and constitutional symptoms. Approximately 7% of individuals with cardiac myxomas have a familial syndrome, Carney complex, an autosomal dominant disorder in which cardiac myxomas occur in the setting of spotty pigmentation of the skin and endocrinopathy. Such cardiac myxomas can occur in all cardiac chambers, may be multicentric, and often recur. We identified a major disease locus for on human chromosome 17q24 and showed that mutations of the PRKAR1 a (R1 a subunit of protein kinase A) gene there cause Carney complex in nearly 2/3 of patients. Most PRKARla mutations result in haploinsufficiency. PRKARla-dependent tumorigenesis in Carney complex appears to require additional somatic mutation. Although loss of PRKARla heterozygosity does occasionally occur, other as yet unidentified(s) genes must play a role in the pathogenesis of Carney complex and cardiac myxomas. Delineation of mechanisms of cardiac tumorigenesis in Carney complex requires the identification of such genes and characterization of experimental models in which to study them. We have now identified a novel locus ("CAR2") with odds of 24,500:1 that contains a second Carney complex disease gene. In addition, we have showed that prkarla haploinsufficient mice exhibit atrial myocyte karyomegaly, and visceral stromal tumors. Therefore, we propose [1] To identify the CAR2 gene that causes Carney complex and cardiac myxomas, [2] To characterize genes that interact with murine prkarl a to cause tumorigenesis, and [3] To assess the contribution of somatic mutation of Carney complex genes to nonfamilial, isolated human cardiac myxomas. We will use a positional cloning-candidate strategy to identify mutations in the CAR2 Carney complex disease gene. We will investigate the effects on murine prkarla dependent tumorigenesis of varied genetic backgrounds and altered gene dosage of other tumor suppressor genes. These studies will establish molecular genetic pathways that lead to tumorigenesis of the heart and other organs in Carney complex and will suggest candidate genes for the pathogenesis of common, nonfamilial cardiac myxomas. Findings will highlight potential targets for treatment of cardiac myxomas for modification of cardiac remodeling in common cardiovascular disorders such as heart failure and ischemic heart disease.